One of the barriers preventing rational and effective treatment of phencyclidine (PCP) overdose is a lack of basic knowledge concerning the mechanism(s) by which PCP exerts its toxic symptoms. Sufficient information has been obtained to indicate PCP's action is multifaceted and shows effects on a number of biochemical components of the central nervous system. Although in vitro PCP has been shown to inhibit cholinesterases, a comprehensive investigation of PCP's cholinergic effects needs to be carried out, particularly with regard to in vivo effects in animal models (rat and mouse). PCP will be admininstered to groups of animals at three different dose levels. The concentration of PCP in blood and brain as a function of time will be carefully studied and correlated with measurements of acetylcholine concentrations, choline acetyltransferase activity, and acetylcholinesterase as well as cholinesterase activity. The results will allow correlation of the PCP levels with each of the components of the cholinergic system. Similar studies will be carried out after treatment with agents known to inhibit (SKF-525A) or stimulate (phenobarbital) the metabolism of PCP. The effects of perturbation of PCP's metabolism on the cholinergic components will differentiate between drug and metabolite activity. Furthermore, the effect of PCP on the high affinity transport system of choline in brain synaptosomes will be studied to evaluate its effect on the rate-limiting step of acetylcholine synthesis. Finally, the modulation of the acute toxicity of PCP by a variety of modifiers of cholinergic systems affecting the cholinergic system will reveal if the effects measured in the previous experiments are contributors to PCP's toxic effects. The results of these experiments will provide definitive information concerning the interaction of PCP with the cholinergic system and treatment of PCP overdose.